Note: Descriptions are shown in the official language in which they were submitted.
10630Z2
This invention relates to the preparation of solid
; medicinal products suitable for use in animals and humans.
More particularly, it is concerned with solid unit dosagé ~-
forms of therapeutically active substances and hydroxypropyl
cellulose. Specifically, it is concerned with solid dosage
; forms or ophthalmic inserts comprising hydroxypropyl
cellulose and medicinal agents which can be used in the
treatment of the eye with a minimum of interference of
; vision.
The usual treatment of various eye conditions
20 consists of applying doses of appropriate medicaments in - -
aqueous suspension solutions or ointments. While such
treatments are satisfactory for treating eye conditions
where only one or several applications of the medicinal
agents are necessary, certain eye conditions require more -
frequent doses and the treatment is inconvenient to the
patient. Recently, it has been proposed to apply the
ophthalmic active medicinal agents in a solid form on an
inert matrix (see for example U.S. Patent 3,710,795). This
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1 method has the disadvantage that the inert matrix must be
2 removed after the drug has been completely released from
3 the matrix. More recently, Loucas et al. [J. of Pharm. sci.,
4 Vol. 61, page 985 (June 1972)] found that the alginic acid
- 5 salt of pilocarpine when administered as a solid state
6 ophthalmic insert provides a greater miotic response than
7 could be obtained by the administration of conventional
8 pilocarpine solutions in the rabbit eye.
9 It is an ob~ect of this invention to provide im-
proved ophthalmic inserts providing prolonged activity and
11 minimizing the frequency of doses necessary in the treatment
12 of various eye conditions. It is a further object to pro-
13 vide a drug-containing ophthalmi~ insert providing a slow
14 but continuing uptake of the medicament in the lacrimal
fluid and providing minimum 109s of the drug into the naso-
16 lacrimal ducts. Another object is to provide an ophthalmic
17 insert which, when administered in the cul-de-sac of the
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18 eye, completely dissolves in the lacrimal fluid and thereby
19 avoids the need for removing any drug depleted material.
Other objects will be apparent from the detailed description
21 of our invention her~inafter provided.
22 In accordance with our invention, these desiderata
23 are achieved with ophthalmic inserts comprising hydroxy-
24 propyl cellulose and an ophthalmic medicament. Suitable
inserts which can be prepared in various ways as will here-
26 inafter be described produce ophthalmic preparations having
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27 prolonged activity on administration. Egress of the drug
28 from the ophthalmic insert is accom~anied by the gelation
29 and finally by the dissolution of the matrix in the lacrimal
`~ ~ 30 fluid, thereby eliminating any need to remove the drug
~`~ 31 depleted matrix before administering a further dose.
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106302Z
Hydroxypropyl cellulose is a non-ionic water
soluble cellulose ether having properties which are uniquely
suitable for use in the preparation of ophthalmic inserts.
Thus, it is water soluble and hence dissolves in the aqueous
lacrimal fluids. In addition, it is thermoplastic and can
therefore be advantageously combined with the ophthalmic
drug using conventional plastic processing procedures such
as compression molding, injection molding and extrusion
prior to unit dose subdivision. Hydroxypropyl cellulose is
available in several polymeric forms, all of which are suit-
able in the preparation of the ophthalmic inserts of the
present invention. Thus, the products sold by Hercules
Incorporated of Wilmington, Delaware under the name KLUCEL --
such as K~UCEL HF, HWF, GF, JF, LF, and EF which are
intended for food or pharmaceutical use are particularly
useful in preparing the new inserts of our invention~
The compositions of this invention can be prepared ; -~
by various methods. Thus, the drug and the hydroxypropyl
cellulose can be dissolved in a suitable solvent and the
solu~ion evaporated to afford a thin film comprising the
hydroxypropyl cellulose and the drug which can then be sub-
divided to prepare suitable inserts containing the desired
amount of the medicament. Alternatively, and in accordance
with a preferred embodiment of our invention, we find that
the inserts can be prepared most conv~aieh~lysus~n~hbhe
thermoplastic properties of the hydroxypropyl cellulose.
For example, the medicament and the hydroxypropyl cellulose
can be warmed together at temperatures between about 150 F.
and ~00F. and the resulting mixture molded to form a thin
film. It is generally p~eferred to prepare the inserts by -
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1 molding or extrusion in accordance with procedures which
2 are well ~nown in the art. The molded or extruded product
3 can then be subdivided to afford inserts of suitable size
4 for administration in the eye. ~or example, castings or
compression molded films having a thickness of about 0.5 mm.
6 to 1.5 mm. can be subdivided to obtain suitable inserts in
7 the form of squares, rectangles, circles, semi-circles, and
8 the like containing the desired amount of active ingredient.
9 Rectangular segments of the cast or compressed film having a
thickness bet~een about 0.5 and 1.5 mm. can be cut to afford
11 shapes such as rectangular plates of 4 x 5-15 mm. or ovals
12 of comparable size. Similarly, extruded rods having a
13 diameter between about 0.5 and 1.5 mm. can be cut into suit-
14 able sections to provide the desired dosage of medicament.
For example, rods of 1.0 to 1.5 mm. in diameter and about
16 10 mm. long are found to be satisfactory. The inserts may
17 also be directly formed by injection molding. All of the
18 ophthalmic inserts prepared in accordance with the present
19 invention should be formed so that they do not have any
sharp edges or corners which could cause damage to the eye.
21 The ocular inserts prepared in accordance with
22 this invention can also contain plasticizers to make the
23 ophthalmic inserts more pliable. Plasticizers suitable for
24 this purpose must, of course, also be completely soluble in
the lacrimal fluids of the eye. Examples of suitable
26 plasticizers that might be mentioned are water, polyethylene
27 glycol, propylene glycol, glycerine, trimethylol propane,
28 di and tripropylene glycol, hydroxypropyl sucrose and the
29 like. Typically, such plasticizers can be present in the
ophthalmic insert in an amount ranging from about 0% to
31 about 30% by weight. A particularly preferred plasticizer
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is water which is present in amounts of at least about 5%
and more preferably at least about 10~. In actual
practice, a water content of from about 10% to about 20% is
preferred since it may be easily accomplished and adds the
desired softness and pliability to the insert.
When plasticizing the solid mecidinal product with
water, the medicinal product is contacted with air having a
relative humidity of at least about 40% until said product
picks up at least about 5% water and becomes softer and
more pliable. In a preferred embodiment, the relative
humidity of the air is from about 60% to about 99% and the
contacting is continued until the water is present in the
product in amounts of from about lC% to about 20%.
Suitable drugs which can be administered by the
inserts of the present invention that might be mentioned are
antibacterial substances such as B-lactam antibiotics, tetra-
cyclines, chloramphenicol, neomycin, gramicidin, bacitracin,
sulfonamides, gentamycin, kanom~rcin, nitrofurazones, and the -
like; antihistaminics and decongestants such as pyrilamine,
chlorpheniramine, tetrahydraz~line, antazoline, and the like;
antiinflammatories such as cortisone, hydrocortisone, beta-
methasone, dexamethasone, fluocortolone, prednisolone, tri-
amcinolone, indomethacin, and the like; miotics and anti-
ch~nesterases such as echothiophate, pilocarpine~ physo- ..
stigmine salicylate, diisopropylfluorophosphate, and the .
like; mydriatics such as atropine, homatropine, scopolamine,
hydroxyamphetamine, and the like; and the other medicaments used
in the treatment of eye conditions. :~-
These drugs or derivatives thereof such as sal~s,
covalent derivatives, for example, esters or amides, or
other therapeutically active forms can be admixed with the .
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hydroxypropyl cellulose in the form of the water soluble
inserts prepared as described above for the treatment of
various eye diseases. These forms are especially advantageous
for the treatment of conditions where prolonged drug adminis-
tration is indicated, for example, in eye diseases or eye
disorders such as uveitis, glaucoma, diseases of the cornea
such as, for example, purulent keratitis, herpes simplex
keratitis, herpes zoster, acne rosacea, interstitial keratitis,
and the like, diseases of the orbit such as exophthalmos and
periostitis and diseases of the coniunctiva such as muco-
purulent coniunctivitis and ophthalmia. Also, this method of
the administration of ophthalmic active drugs can be used when
post-operative treatment is needed after retinal or cataract
surgery.
The method of administering drugs as a water soluble
insert is especially useful in the administration of pilo-
carpine to treat glaucoma, a condition characterized by an
increase in intraocular pressure. The present treatment of
this condition involves the use of solutions of pilocarpine - -
¦ 20 acid salts which are administered to the eye in the form of
¦ drops at frequent intervals. By inserting the ophthalmic
inserts of the present invention, a miotic response of up to
9-10 hours may be obtained in rabbits compared to the short
response of 2-4 hours obtained by the administration of drops.
I The pilocarpine can be administered preferably in the form of
¦~ acid salts of this drug such as the hydrochloride, alginate,
pam~ate, and the l~ke. A particularly useful salt for the
purposes of the present invention is the pamoic acid salt of
pilocarpine which is a new compound and which is obtalned by
reacting pamoic acid with pilocarplne in solution. The
ophthalmic inserts of the present invention can contain up to
about 35X by weight of pilocarpine to afford a dose of about
1-6 mgs. of pilocarpine per insert.
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10630ZZ
1 In general the ophthalmic inserts of the present
2 invention will contain from about 0.1 to about 35% of the
3 medicament, from about 65 to about 99.9% of hydroxypropyl
4 cellulose and from 0 to about 30% of plasticizer, preferably
water. In special situations, however, the amounts may be
6 varied to increase or decrease the dosage schedule.
7 The following examples describe specific methods
8 of preparing the novel ophthalmic inserts of our invention
9 and are provided to illustrate specific embodiments of our
invention.
11 EXAMPLE 1
-
12 The following aqueous solutions were prepared:
13 Solution A
.
14 Pilocarpine base 2.08 g.
15 Alginic acid ~ 2.42 g.
16 Hydroxypropyl cellulose (RLUCEL GF) 0.45 g.
17 Water 30 ml.
18 Solution B
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19 Pilocarpine base 2.08 g.
20 Alginic acid ~ 2.42 g.
21 Hydroxypropyl cellulose (~LUCEL HF) 0.45 g.
22 Water 30 ml.
23 Solution C
24 Pilocarpine base 2.08 g.
25 Alginic acid ~ 2.42 g.
`26 Hydroxypropyl cellulose (RLUCEL JF) 0.45 g.
27 Water 30 ml.
28 Thin films were prepared by casting films from
29 these solutions and then cutting the dried films into
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rectangular shapes, approximately 3 by 10 mm. The in vivo
`~ 31 di~appearance time and the total miotic action of these
32 ophthalmic inserts were determined as follow~s ~-
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1 Randomized series of six male and female New
2 Zealand albino rabbits weighing 3-3.5 ~g., approximately
3 4-5 months of age, were used. The animals were kept in
4 restraint boxes in a room with a steady light of weak
intensity. The naive animals were accustomed to the
6 experimental conditions (laboratory, restraint boxes ...)
7 once before time of testing. The same rabbits were re-used
8 with at least 14 days rest between two testings; they were
9 finally eliminated after five times. The animals were
accustomed to the environment for 1 hour, and after initial
11 measurements, the compounds to be studied were administered
12 (solutions, rods, discs, ointment ...) into the conjunctival
13 sac of one eye and the other non-treated eye was the control.
14 The pupil measurements were made 5, 30, 90, 210 and 360
minutes after treatment. The average pupil diameters and
16 confidence limits for PC 0.05 of each series (6 rabbits)
17 were given. The pupil diameter was measured with a LUNEAU
18 and COFFIGNON pupillometer whose principle of operation con-
19 sists in superimposing the virtual image of a red light beam
of variable diameter into the plane of the iris. With an
21 adjustable diaphragm, one adjusts the diameter of the bundle
22 of red light rays to coincide with that of the pupil. The
23 diameter of the diaphragm is recorded directly in milli-
24 meters. The results of these tests are shown in the follow-
2S ing table:
26 Preparation Disappearance Mg. of Total Miotic
27 No. Time Pilocarpine Activity ~ Insert/
28 (minutes) per Insert Total Miotic
29 Activity~ Solution
A 10 Ct C 30 4.01 23 - 1.11
~;7
31 B 120C t C 240 4.56 26,3 = 1.56
32 C 240 C t~'300 5.,7 34.1 = 2.08
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1 ~ otal miotic activity is an equivalent term for total
2 biological response and is expressed as the area under
3 the curve representing pupil size change from the time
4 the dose was administered to the time for the pupil size
to return to the control diameter. The area of the re-
J 6 sponse curve is obtained from a plot of the pupil size
7 versus time for the treated eye versus the control eye.
8 ~ ffect is significantly better than solution after
9 210 minutes.
EXAMæLE 2
11 A mixture of 25 g. of 60 mesh pilocarpine pamoate
12 and 75 g. of 60 mesh hydroxypropyl cellulose (KLUCEL HF) are
13 mixed thoroughly using conventional dry powder mixing pro-
14 cedures such ac mortar and pestal, twin shell blender,
planetary mixer, and the like. The mixture is then passed
16 through a 30 mesh screen and remixed. A small amount (2 to
17 5 g.) of the mixture is then placed in the center of a clean
18 dry aluminum sheet having a thickness of 0.2755 in., the
19 surface of which is coated with a lubricant such as aero-
solized lecithin and a thickness regulator (shim) of about
21 1 mm. is placed in each of the four corners of the aluminum
22 sheet. A second lubricated 0.2755 in. thick aluminum sheet
23 is placed over the first sheet and transferred to a hydraulic
24 press, such as a Model B Carver Press, between two 6 x 6 in.
platens equipped for heating and cooling; the top and bottom
26 platens having been previously preheated to a temperature of
27 200F. The press is then closed and the material subjected
28 to a pressure of 10,000 lb~. gauge while maintaining the
29 platens at the same temperature. After 1 minute, cold water
is circulated in the platens to cool the product while the
31 pressuxe is being maintained. After about 2 minutes, the
32 pressure is released and the product in the form of a wafer-
33 thin sheet is removed. Is is then cut into small rectangles
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1 approximately 10 mm. by 4 mm. having a thickness of about
2 0.8 mm. and containing about 2 to 4 mg. of pilocarpine per
3 unit dose.
4 The ophthalmic inserts so obtained were tested for
miotic activity in rabbits using the procedures described in
6 Example 1. At the same time, a conventional solution of
7 pilocarpine comprising an equivalent dose of pilocarpine
8 was administered to one group of rabbits. The results of
9 these tests are shown in the following table:
Mean Pupil Diameters - mm.
11 Rectangular
12 Time Conventional Pilocarpine
13 (hrs.) ControlPilocarpine Solution Pamoate Inserts
14 0 7.5
1/2 7.3 5.2 5.2
16 1 1/2 7.3 5.6 4.8
17 3 1/2 7.4 6.7 5 0
18 6 7.5 7.4 5 5
19 7 7.4 --- 5.7
8 7.4 --- 5.6
21 9 7.4 --- 6.3
22 10 7.4 --- 6.8
23 The above table shows the prolonged miotic effect
24 obtained when the pilocarpine is administered in the form of
the rectangular insert formed with the hydroxypropyl
26 cellulose.
27 The above ophthalmic inserts are placed in a
28 cabinet and contacted for 2 days with air at room tempera-
29 ture and a relative humidity of 88%. The ophthalmic inserts
30 having an initial weight of about 18 mgs. increase to a --
31 weight of 20 mgs. in the two-day period showing a pickup of
32 2 mg8. of water or about 11% based on the total weight of
33 the insert. The plasticizing effect of the water makes the
34 insert muoh softer and pliable.
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E~AMP E 3
The mixture of pilocarpine pamoate and hydroxypropyl
cellulose prepared as described in Example 2 is used for
the preparation of an extruded filament in conventional
extrusion equipment in the following manner.
The heater control of a Custom Scientific
Instrument Mini-Max Molder (Model CS-1~3) is set at 200c.
After the apparatus is sufficiently heated, the drive switch
for the rotor is turned on and approximately 0. 5 g. of the
bulk powdered mixture is fed into the cup. A filament of
the desired diameter (less than 1 mm. to 2 mm.) is obtained
by drawing the extrudate with steady p~lling; the force
exerted on the hot extrudate determining the diameter of the
filament. Filaments in the form of rods prepared in this
way are cut in lengths of about 10 mm. having a pilocarpine
content of 1.9 mg. These are tested for miotic response in
the rabbit eye using the test procedure described in
Example 1 with the results shown in the following table;
Mean PuPil Diameter - mm.
Time
(hrs.~ ControlExtruded Filament
o 7.5 ~
1/2 7.4 5.3
/2 7.3 5.3
3 l/2 7.4 5.9
6 7.~ 5.5
7 7.5 5.7
~ 7.5 6.0
9 7.6 6.2
The above ophthalmic inserts are placed in a
cabinet and contacted for 2 days with air at room tempera-
ture and a relative hymidity of ~%. The ophthalmic inserts
having an initial weight of about 1~ mgs. increase to a
weight of 20 mgs. in the two-day period showing a pickup of
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1 2 mgs. of water or about 11% based on the total weight of
2 the insert. The plasticizing effect of the water makes
3 the insert much softer and pliable.
4 The ophthalmic inserts can also be injection
molded using the same equipment and a single or multi-
6 cavity mold.
7 EXAMPLE 4
8 A mixture of 16.25 parts by weight of 60 mesh
9 pilocarpine nitrate and 83.38 parts by weight of hydroxy-
propyl cellulose are thoroughly mixed and to this mixture
11 is added 8.37 parts of propylene glycol in a high shear
12 mixer. A small amount of resulting mixture is then com-
13 pressed using the procedures described in Example 2 to form
14 a thin solid sheet of the mixture which is cut into rectan-
gular shaped inserts about 10 mm. by 4 mm. having a thicl~-
16 ness of about 0.8 mm. The ophthalmic inserts containing 3.4
17 mg. of pilocarpine so obtained were tested in the rabbit eye
18 for miotic response with the following results:
19 Mean Pupil Diameter - mm. _ __
.
20Time
21(hrs.) Control Rectangular Insert
22 0 7.3 ~
231/2 7.2 4.7
241 1/2 7.2 4.6
253 1/2 7.3 4.6
26 6 7.3 5.9
27 7 7.3 5.9
28 8 7.3 6.2
29 9 7.3 6.4
3010 7.3 6.9
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10630ZZ
EXAMPLE 5
A mixture consisting of 17.5 parts by weight of
pilocarpine alginate, 74.25 parts by weight of hydroxypropyl
cellulose (KLUCEL~ F), and ~.25 parts by weight of propylene
glycol are mixed following the procedures described in
Example 4. The resulting mixture is compressed following
the procedures described in Example 2 to obtain a thin film
which is cut to form rectangular inserts 10 X 4 mm. and about
0.~ mm. thick. These inserts containing about 2.2 mg. of
pilocarpine are tested in the rabbit eye by the test pro-
cedure described in Example 1 with the following results:
TimèMean PuPil Diameter ~ mm.
(hrs.) Control Rectan~ular Insert
0 7.3
1/2 7.3 4.3
1 1/2 7.3 4.5
3 1/2 7.3 ~.
6 7.3 5.3
7 7.5 6.2
~ 7.7 6.9
9 7.5 6.9
EXAMPLE 6
The miotic effect Or a standard solution of pilo-
carpine and a solid pilocarpine alginate insert prepared as
described by Loucas et al. are compared using the rabbit
test procedure described in Example l. In these tests
dosages of 9;7,'mg. o~ pilocarpine are used. The miotic
responses are shown in the following table:
Mean Pupil Diameter - mm.
Time -Equivalent Dose Of Pilocarpine
~h~8. ) Control PilocarPine Solution Al~inate
, :
1/2 7 5 ~.6
1 1/2 7.5 4.9 4.~ -
3 1/2 7.5 7.2 5.3
6 7.5 7.4 6.6
7 7.5 --- 7.2
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1063022
EXAMPLE 7
The pamoic acid salt of pilocarpine used in Example
2 is prepared as follows:
The pilocarpine base 20.7 9. is dissolved in 20 ml.
of water and a stoichiometric amount 19.3 9. of pamoic acid is
added. The mixture is stirred for about 3 hours until a homo-
genous brown oily mixture results. The mixture is placed in a
heated (50-60C) vacuum (22 in. hg.) desiccator. Each day, the
container is removed from the desiccator and the portion of the
oil which has dried on the surface is removed and ground to a
powder. The container with the remaining liquid oily mixture
is again placed in the heated vacuum desiccator. This is
repeated until all of the oil is dried and removed from the
container giving a yield of over 90%.
The analytical data is as follows: 1) Moisture - 3.15% K.F.
2) Elemental analysis
Calc. %Exper., %Calc. %, corrected for water
N6.986.8, 7.14 (2 runs) 6.76
C67.3164.75, 65.01 (2 runs)65.19
H5.776.17, 6.15 (2 runs) 5.95
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